Incidence of ischemic cardiac diseases caused by arteriosclerosis, especially, coronary arteriosclerosis, such as angina pectoris, and myocardial infarction are recently on the increase. Pathological tissue images of arteriosclerosis mainly show local intimal thickening and diminished elasticity. As a result, circulation is disturbed, and nutrients and oxygen are insufficiently supplied to myocardial tissues, leading to the above-mentioned conditions.
Many important findings have been made regarding the pathogenesis of intimal thickening. A typical example is that the thickened intima primarily constitutes of smooth muscle cells that migrated from tunica media (Parker, F., Amer. J. Pathol., 1960, 36, 19-53; and Webster, W. S., S. P. Bishop & J. C. Geer, Amer. J. Pathol., 1974, 76, 245-264). Moreover, the hypothesis that arteriosclerosis develops as a result of the injury-repairing reaction (Ross, R., N. Engl. J. Med., 1986, 314, 488-500) is the base of understanding on arteriosclerosis even now.
Percutaneous transluminal coronary angioplasty (PTCA), a treatment in which a blood vessel constricted by such an intimal thickening is inflated by a balloon and physically expanded, is a common treatment at present. PTCA surgery has proved to be remarkably effective with a 90% or higher recovery rate. However, restenosis occurs with a frequency of 30 to 60% at the same site within 6 months or less following PTCA. It is pathologically recognized that restenosis is the result of an excessive repairing mechanism, the excessive neointima formation at the artery wall of the injured site (Nobuyoshi, M. et al: J. Am. Coll. Cardiol. 17: 433-439, 1991). It has also been confirmed that this neointima forms from tunica media-derived smooth muscle cell migration and proliferation, and hyperplasia of the extracellular matrix. The following molecular biological mechanism in the neointima formation process is known. First, a transformation of blood vessel smooth muscle cells from a contractile to a synthetic phenotype is observed. Further, the following substances that induce cell proliferation, and overexpression of their receptors, have been reported:                various growth factors, such as platelet-derived growth factor (PDGF) and Fibroblast growth factor (FGF);        cytokines, such as interleukin and tumor necrosis factor α (TNFα);        Angiotensin II; and        Thrombin.        
Based on these backgrounds, it could be hypothesized that restenosis can be prevented by inhibiting the migration and proliferation of blood vessel smooth muscle cells. Thus, many pharmaceuticals were examined for their inhibitory effects on intimal proliferation using animal experiments. Effective ones were clinically tested, however, no effectiveness could be clinically established for any of these pharmaceuticals (Circulation., 1992, 86, 100-110; and Weint raub, W. S. et al., N. Engl. J. Med., 1994, 331, 1331-1337).
Midkine (MK) was discovered as a gene product, expression of which is induced at the early stage of the differentiation induction process of embryonic tumor cells by retinoic acid (Kadomatsu, K. et al., Biochem. Biophys. Res. Commun., 1998, 151, 1312-1318). Pleiotrophin (PTN, or HB-GAM) was discovered as a binding protein having neurite elongation ability in the brains of newborn rats (Rauvala, H., 1989, EMBO J., 8, 2933-2941). MK and PTN are heparin-binding proteins which control cell proliferation, survival, and differentiation in the developmental process (Tomomura, M. et al., J. Biol. Chem., 1990, 265, 10765-10770; Li, Y. et al., Science, 1990, 250, 1690-1694; Rauvala, H., EMBO J., 1989, 8, 2933-2941; Wellstein, A. et al., J. Biol. Chem., 1992, 267, 2582-2587), have about a 50% sequence homology (Tomomura, M. et al., J. Biol. Chem., 1990, 265, 10765-10770; Kuo, M. et al., J. Biol. Chem., 1990, 265: 18749-18752; and Tsutsui, J. et al., Biochem. Biophys. Res. Commun., 1991, 176, 792-797), and form the MK family (Muramatsu, T., Dev. Growth Differ., 1994, 36, 1-8).
A mature MK protein is a protein with a molecular weight of 13,000, comprising 121 amino acids rich in basic amino acids and cysteins. Its function is various, including, for example, promoting survival of nerve cells, neurite elongation, accelerating fibrinolysis in endothelial cells of blood vessels, and transformation of NIH3T3 cells. In addition to these, involvement of MK in tissue reconstitution has been recently drawing attention. Expression of MK was observed in gliocytes around brain infarction nidi, mainly in the epithelial side of the region where interaction between the epithelium and stroma takes place during development, etc.
However, no relationship between arteriosclerosis and restenosis after PTCA and MK protein has been reported.